QGC606: A Best-in-Class Orally Active Centrally Acting Aminopeptidase A Inhibitor Prodrug for Treating Heart Failure Following Myocardial Infarction.

BACKGROUND: Blockade of brain renin-angiotensin system (RAS) overactivity by firibastat, the first centrally acting aminopeptidase A (APA) inhibitor prodrug, has already demonstrated its effectiveness in improving cardiac function after myocardial infarction (MI). We developed QGC606, a more potent and more selective APA inhibitor prodrug and studied its effects after long-term oral administration in mice post-MI. METHODS: Two days after MI induced by the left anterior descending artery ligation, adult male mice were randomized into 4 groups to receive oral treatment during 4 weeks with vehicle; QGC606; firibastat; or the angiotensin-I converting enzyme inhibitor ramipril, used as positive control. RESULTS: Four weeks post-MI, brain APA was overactivated in vehicle-treated MI mice. QGC606 treatment normalized brain APA hyperactivity to control values measured in sham-operated mice. Four weeks post-MI, QGC606-treated mice had higher left ventricular (LV) ejection fractions, significantly smaller LV end-systolic diameter and volume, significantly lower HF biomarkers mRNA expression (Myh7 and Anf) and plasma N-terminal pro B-type natriuretic peptide (NT-pro-BNP) and noradrenaline levels than saline-treated mice. QGC606 treatment significantly improved the dP/dt max and min, LV end-diastolic pressure without affecting blood pressure (BP), whereas we observed a decrease in BP in ramipril-treated mice. We observed also a reduction of cardiac fibrosis, highlighted by lower connective tissue growth factor mRNA levels and a reduction of both the fibrotic area and MI size in QGC606-treated mice. CONCLUSIONS: Chronic oral QGC606 administration in post-MI mice showed beneficial effects in improving cardiac function and reducing cardiac remodeling and fibrosis but, unlike ramipril, without lowering BP.

Apelin and Vasopressin: The Yin and Yang of Water Balance.

Apelin, a (neuro)vasoactive peptide, plays a prominent role in controlling body fluid homeostasis and cardiovascular functions. Experimental data performed in rodents have shown that apelin has an aquaretic effect via its central and renal actions. In the brain, apelin inhibits the phasic electrical activity of vasopressinergic neurons and the release of vasopressin from the posterior pituitary into the bloodstream and in the kidney, apelin regulates renal microcirculation and counteracts in the collecting duct, the antidiuretic effect of vasopressin occurring via the vasopressin receptor type 2. In humans and rodents, if plasma osmolality is increased by hypertonic saline infusion/water deprivation or decreased by water loading, plasma vasopressin and apelin are conversely regulated to maintain body fluid homeostasis. In patients with the syndrome of inappropriate antidiuresis, in which vasopressin hypersecretion leads to hyponatremia, the balance between apelin and vasopressin is significantly altered. In order to re-establish the correct balance, a metabolically stable apelin-17 analog, LIT01-196, was developed, to overcome the problem of the very short half-life (in the minute range) of apelin in vivo. In a rat experimental model of vasopressin-induced hyponatremia, subcutaneously (s.c.) administered LIT01-196 blocks the antidiuretic effect of vasopressin and the vasopressin-induced increase in urinary osmolality, and induces a progressive improvement in hyponatremia, suggesting that apelin receptor activation constitutes an original approach for hyponatremia treatment.

LIT01-196, a Metabolically Stable Apelin-17 Analog, Normalizes Blood Pressure in Hypertensive DOCA-Salt Rats via a NO Synthase-dependent Mechanism.

Apelin is a neuro-vasoactive peptide that plays a major role in the control of cardiovascular functions and water balance, but has an in-vivo half-life in the minute range, limiting its therapeutic use. We previously developed LIT01-196, a systemically active metabolically stable apelin-17 analog, produced by chemical addition of a fluorocarbon chain to the N-terminal part of apelin-17. LIT01-196 behaves as a potent full agonist for the apelin receptor and has an in vivo half-life in the bloodstream of 28 min after intravenous (i.v.) and 156 min after subcutaneous (s.c.) administrations in conscious normotensive rats. We aimed to investigate the effects of LIT01-196 following systemic administrations on arterial blood pressure, heart rate, fluid balance and electrolytes in conscious normotensive and hypertensive deoxycorticosterone acetate (DOCA)-salt rats. Acute i.v. LIT01-196 administration, in increasing doses, dose-dependently decreases arterial blood pressure with ED50 values of 9.8 and 3.1 nmol/kg in normotensive and hypertensive rats, respectively. This effect occurs for both via a nitric oxide-dependent mechanism. Moreover, acute s.c. LIT01-196 administration (90 nmol/kg) normalizes arterial blood pressure in conscious hypertensive DOCA-salt rats for more than 7 h. The LIT01-196-induced blood pressure decrease remains unchanged after 4 consecutive daily s.c. administrations of 90 nmol/kg, and does not induce any alteration of plasma sodium and potassium levels and kidney function as shown by the lack of change in plasma creatinine and urea nitrogen levels. Activating the apelin receptor with LIT01-196 may constitute a novel approach for the treatment of hypertension.

A metabolically stable apelin-17 analog decreases AVP-induced antidiuresis and improves hyponatremia.

Apelin and arginine-vasopressin (AVP) are conversely regulated by osmotic stimuli. We therefore hypothesized that activating the apelin receptor (apelin-R) with LIT01-196, a metabolically stable apelin-17 analog, may be beneficial for treating the Syndrome of Inappropriate Antidiuresis, in which AVP hypersecretion leads to hyponatremia. We show that LIT01-196, which behaves as a potent full agonist for the apelin-R, has an in vivo half-life of 156 minutes in the bloodstream after subcutaneous administration in control rats. In collecting ducts, LIT01-196 decreases dDAVP-induced cAMP production and apical cell surface expression of phosphorylated aquaporin 2 via AVP type 2 receptors, leading to an increase in aqueous diuresis. In a rat experimental model of AVP-induced hyponatremia, LIT01-196 subcutaneously administered blocks the antidiuretic effect of AVP and the AVP-induced increase in urinary osmolality and induces a progressive improvement of hyponatremia. Our data suggest that apelin-R activation constitutes an original approach for hyponatremia treatment.

[Physiological role of the apelin receptor: implication in body fluid homeostasis and hyponatremia]. / Rôle physiologique du récepteur de l'apéline : Implication dans le maintien de l'équilibre hydrique et de l'hyponatrémie.

Apelin, a vasoactive neuropeptide, its receptor and arginine-vasopressin (AVP, antidiuretic hormone) are co-localized in magnocellular vasopressinergic neurons. In the kidney, the apelin receptor is present in glomerular arterioles and the collecting duct (CD) where the AVP type 2 (V2-R) receptors are located. Apelin exerts an aquaretic action both by its inhibitory effect on the phasic electrical activity of vasopressinergic neurons and the secretion of AVP into the bloodstream and by its direct actions at the kidney level resulting in an increase in the renal microcirculation and the inhibition of the antidiuretic effect of AVP mediated by V2-R in the CD. Plasma apelin and AVP are conversely regulated by osmotic stimuli in both humans and rodents, showing that apelin is involved with AVP in maintaining body fluid homeostasis. Clinically, in patients with inappropriate antidiuresis syndrome (SIAD), the apelin/AVP balance is altered, which contributes to water metabolism defect. Activation of the apelin receptor by the metabolically stable apelin-17 analog, that increases aqueous diuresis and moderately water intake and gradually corrects hyponatremia, may constitute a new approach for the treatment of SIAD.

Title: Rôle physiologique du récepteur de l'apéline : Implication dans le maintien de l'équilibre hydrique et de l'hyponatrémie. Abstract: L'apéline, un neuropeptide vasoactif, son récepteur (Apéline-R) et l'arginine-vasopressine (AVP, hormone antidiurétique) sont co-localisés dans les neurones magnocellulaires vasopressinergiques. Dans le rein, l'Apéline-R est présent dans les artérioles glomérulaires et le canal collecteur (CD) où sont aussi localisés les récepteurs de l'AVP de type 2 (V2-R). L'apéline exerce une action aquarétique par son effet inhibiteur sur l'activité électrique phasique des neurones vasopressinergiques et la sécrétion systémique de l'AVP dans la circulation sanguine, et par son action directe au niveau du rein. Dans cet organe, elle augmente la microcirculation locale et inhibe, au niveau du CD, l'effet antidiurétique de l'AVP médié par les V2-R. L'apéline et l'AVP dans le plasma sont inversement régulées par les stimuli osmotiques aussi bien chez l'Homme que chez le rongeur, montrant que l'apéline participe avec l'AVP au maintien de l'équilibre hydrique. Sur le plan clinique, chez les patients atteints du syndrome d'antidiurèse inappropriée (SIAD), l'équilibre apéline/AVP est altéré, ce qui contribue au défaut du métabolisme de l'eau. L'activation de l'Apéline-R par un analogue métaboliquement stable d'une des isoformes de l'apéline, l'apéline-17, en augmentant la diurèse aqueuse et modérément la prise d'eau, et en corrigeant progressivement l'hyponatrémie, pourrait constituer une nouvelle approche pour le traitement de cette pathologie.